The present invention relates to a suppressing agent of angiogenesis, wherein the agent contains dienogest as the effective ingredient.
Dienogest is the International Nonproprietary Name (INN) of a known compound with the following structure (17 xcex1-cyanomethyl-17 xcex2-hydroxy-estra-4, 9(10)-dien-3-one) represented by the following formula (1). 
The properties of the compound and a method for synthesizing the compound are generally described by Shubert, et al., Natural Products Chemistry 1984, Elsevier Science Publishers eds., 1985, pp. 143-158.
Dienogest has been known to have progestational activity. In Germany, a combined drug of dienogest with ethinylestradiol has been introduced as an oral contraceptive into market. Additionally, the clinical development of dienogest as a therapeutic agent of endometriosis is ongoing (Kohler et al., Archives of Gynecology and Obstetrics, Vol. 254, pp. 594-595, 1993), and experimental reports have been issued to demonstrate the carcinostatic action of dienogest on uterine cancer and breast cancer (Katsuki et al., Japanese Patent Laid-open No. Hei 7-188026; Katsuki, et al., Cancer, Vol. 79, pp. 169-176, 1997). However, no report has been published yet to tell that dienogest has an action to suppress angiogenesis.
Angiogenesis is involved in normal physiological phases in humans and animals, such as embryo development and ovulation or placenta formation due to the female sex cycle and is also responsible for wound healing and the repair process of inflammation. Furthermore, it has been known that angiogenesis is also involved in many of pathologic conditions caused by rapid growth and proliferation of capillary vessel, leading to severe damage on tissues. The diseases caused by such pathologic increase of capillary vessel is called as so-called angiogenic diseases (Folkman et al., Science, Vol. 235, pp. 442-447, 1987). As the angiogenic diseases, the following diseases have been known; intraocular angiogenic diseases (intraocular angiogemic disease) (Ishibashi, T. xe2x80x9cWhat is intraocular angiogenesis?xe2x80x9d ed. Ishibashi, T. Intraocular Angiogenic Diseases, p. 2, Medical View Co., Tokyo, 1994) including diabetic retinopathy, occlusion of retinal vein, premature retinopathy, age-related macular degeneration, neovascular glaucoma, Eales""s disease or terior lens fibroplasia, angiogenesis following cornea transplantation, glaucoma and trachoma and the like in the field of ophthalmology; psoriasis and pyogenic granuloma and the like in the field of dermatology; angioma and fibrous angioma and the like in the field of pediatrics; hypertrophic scar and proud flesh and the like in the field of surgery; rheumatic arthritis and edema sclerosis and the like in the field of internal medicine; and arteriosclerosis and myocardial infarction and the like in the field of cardiac diseases. It has additionally been known well that angiogenesis is involved in the onset and progress of tumor which generally is not called as angiogenic disease. The diseases accompanied by such abnormal angiogenic escalation have been treated in various manners, but all the diseases are refractory diseases. Therefore, a useful compound as a prophylactic or therapeutic agent therefor has been demanded.
As the substance with an activity to suppress angiogenesis, the following substances have been known; sulfated polysaccharides, platelet factor-4 (PF-4), pentosan polysulfate, TNP-470 (fumagillin derivative), irsogladine, minocycline and the like. However, their actions on the suppression of angiogenesis are not sufficient. Suppressing agents of angiogenesis are reasonable therapeutic agents of diseases accompanied by abnormality in angiogenesis. Hence, the development of a better suppressing agent of angiogenesis has been desired.
It has already been known that medroxyprogesterone acetate (abbreviated as xe2x80x9cMPAxe2x80x9d hereinafter) has an action to suppress angiogenesis. However, the angiogenesis suppressing action of MPA is not satisfactory. It is doubtful whether or not routine clinical dose thereof can exert the effect. At a high dose, MPA induces serious side effects due to the hormone actions as well as thrombosis. It has also been reported that FMPA (9-fluoromedroxyprogestreone acetate) has an action of inhibiting angiogenesis (Sugino et al., Chemical Pharmaceutical Bulletin, Vol. 45, No.2, pp. 421-423, 1997; Hibino et al., WO95/26974). It is found that the compound free of any hormone action is a stronger suppressing agent of angiogenesis than MPA. Nevertheless, the compound has not yet reached the stage of clinical development.
The angiogenesis suppressing action of MPA is believed not to be derived from progestin action (Yamamoto et al., International Journal of Cancer, Vol. 56, pp. 393-399, 1994; JIKIHARA et al., American Journal of Obstetrics and Gynecology, Vol. 167, No.1, pp. 207-211, 1992).
It has been reported that the FMPA described above is free of any hormone action and that progesterone does not have any activity on angiogenic suppression in a rabbit cornea assay system (Yamamoto, supra.). From structural standpoint, MPA and FMPA have a pregnane skeleton, so they are different from dienogest with an estrane skeleton.
Those capable of exerting angiogenic suppressing actions in the presence of heparin and with no activity of glucocorticoid or mineral corticoid are known as so-called angiostatic steroids (Crum et al., Science, Vol. 230, pp. 1375-1378, 1985). However, progesterone does not exert any action on angiogenic suppression although the steroid does not have any activity of glucocorticoid or mineral corticoid. On contrast, hydrocortisone as one of glucocorticoids exerts an angiogenesis suppressing action in the absence of heparin (HORI et al., British Journal of Pharmacology, Vol. 118, pp. 1584-1591, 1996). In addition to what has been described insofar, the structural specificity of such angiostatic steroids has not yet been elucidated. Accordingly, the concept thereof is not evident.
In such circumstances, the development of a highly effective prophylactic or therapeutic agent of diseases accompanied by abnormal angiogenic escalation has been demanded, which agent can be administered with less side effects for a prolonged term.
In intraocular angiogenic diseases, diabetic retinopathy, and particularly proliferative retinopathy rapidly cause the elimination of vision, characterized in that the diseases initially start in angiogenic symptoms on retina, and then, fibrous tissues are formed therearound and the grown fibrous tissues shrink with cicatrix, which causes retinal detachment and vitreous bleeding due to the transection of retinal vessel. Age-related macular degeneration is the disease of which the incidence is the highest in the diseases that cause choroidal angiogenesis, and the therapy by photocoagulation is only established at present. However, there is a possibility that the therapy itself impairs vision. Therefore, an ideal therapeutic method has been desired. If left to stand, malignant tumor proliferates in a host as long as the host is viable, and the proliferation makes an invasive proliferation pattern, with almost no exception. Without any treatment, the tumor then turns metastatic and finally kills the host to death. Rheumatic arthritis causes inflammation of synovial membrane at an early stage, but at its advanced stage, the disease damages cartilage and bone, while the disease deforms and dislocates joints, leading to the loss of flexibility because of the osseous rigidity. Arteriosclerosis is divided as the following three conditions; atherosclerosis, minimal arteriosclerosis and Moncheberg""s type arteriosclerosis. Essentially, the disease encompasses clinically pathologic conditions with the etiology in arterial stenosis, occlusion or dilation and puncture, which are caused by arteriosclerosis. Atherosclerosis with the highest clinical incidence is observed in elastic-type arteries of broad type and muscular-type arteries of medium type, with the principal lesion lying in the intima, and the lesion then progresses into fatty stripe, fibrous erythema and complex lesions. At the most advanced stage of the complex lesion, ulcer formation, calcium deposition, bleeding and thrombus formation are observed. The present invention can overcome at least one of the symptoms described above.
The present inventors have made investigations to solve the problems. The inventors have found that dienogest unexpectedly has a strong action to suppress angiogenesis. The action is so strong that the agent might be applicable to the therapeutic treatment of diseases with abnormal angiogenic escalation as well as solid carcinoma. Additionally, the inventors have found that dienogest can exert the strong activity even if used singly, with no use of any agent in combination with the drug. Thus, the present invention has been achieved.
A first aspect of the present invention is a suppressing agent of angiogenesis, wherein the agent contains dienogest or a solvate thereof as the effective ingredient.
A second aspect of the present invention is a prophylactic and/or therapeutic agent of angiogenic diseases, wherein the agent contains dienogest or a solvate thereof as the effective ingredient.
A third aspect of the present invention is a prophylactic and/or therapeutic agent of angiogenic diseases, wherein the agent contains dienogest or a solvate thereof as the effective ingredient, particularly a prophylactic and/or therapeutic agent of intraocular angiogenic diseases, rheumatic arthritis, and arteriosclerosis.
A fourth aspect of the present invention is a prophylactic and/or therapeutic agent of sex hormone-non-dependent tumor, wherein the agent contains dienogest or a solvate thereof as the effective ingredient.
A fifth aspect of the present invention is a prophylactic and/or therapeutic agent of diseases accompanied by abnormal angiogenic escalation, wherein the agent contains dienogest or a solvate thereof as the effective ingredient, particularly a prophylactic and/or therapeutic agent of intraocular angiogenic diseases, rheumatic arthritis, and arteriosclerosis.
A six aspect of the present invention is a prophylactic and/or therapeutic agent of diseases accompanied by abnormal angiogenic escalation, wherein the agent contains dienogest or a solvate thereof as the effective ingredient, particularly a prophylactic and/or therapeutic agent of sex hormone-non-dependent tumor.
A seventh aspect of the present invention is a prophylactic and/or therapeutic agent of intraocular angiogenic diseases, rheumatic arthritis, and arteriosclerosis, wherein the agent contains dienogest or a solvate thereof as the effective ingredient.
An eighth aspect of the present invention is a suppressing agent of angiogenesis, wherein the agent contains dienogest or a solvate thereof as the effective ingredient and the agent is useful as a chemical reagent.
A ninth aspect of the present invention is the suppressing agent of angiogenesis to be used in combination with other compounds.
Each of the first to ninth aspects of the present invention mentioned above also includes a prophylactic and/or therapeutic method of each disease by a pharmaceutical composition that contains dienogest or a solvate thereof as the effective ingredient, as well as a use of dienogest or a solvate thereof in the production of an prophylactic and/or therapeutic agent of each disease.